The present invention relates to certain compounds of the formula (I), depicted below, having utility as hypoglycemic agents, methods for their use and pharmaceutical compositions containing them.
In spite of the early discovery of insulin and its subsequent wide-spread use in the treatment of diabetes, and the later discovery and use of sulfonylureas (e.g. chlorpropamide, tolbutamide, acetohexamide, tolazamide) and biguanides (e.g. phenformin) as oral hypoglycemic agents, the treatment of diabetes remains less than satisfactory. The use of insulin, necessary in about 10% of diabetic patients in which synthetic hypoglycemic agents are not effective (Type I diabetes, insulin dependent diabetes mellitus), requires multiple daily, usually self injection. Determination of the proper dosage of insulin requires frequent estimations of the sugar in the urine or in the blood. The administration of an excess dose of insulin causes hypoglycemia, with effects ranging from mild abnormalities in blood glucose or coma, or even death. Treatment of non-insulin dependent diabetes mellitus (Type II diabetes) usually consists of a combination of diet, exercise, oral agents, e.g., sulfonylureas, and in more severe cases, insulin. However, the clinically available hypoglycemics are unfortunately fraught with other toxic manifestations which limit their use. In any event, where one of these agents may fail in an individual case, another may succeed. A continuing need for hypoglycemic agents, which may be less toxic or succeed wbere others fail, is clearly evident.
In addition to the hypoglycemic agents cited above, a variety of other compounds have been reported to possess this type of activity, as reviewed recently by Blank [Burger's Medicinal Chemistry, Fourth Edition, Part II, John Wiley and Sons, N.Y. (1979), pp. 1057-1080].
U.S. Pat. No. 4,342,771 discloses a class of oxazolidinedione hypoglycemic agents of the general formula ##STR1## where R.sup.a is H or certain acyl groups and R.sup.b is certain mono- or bicyclic heterocyclic groups.
European Patent Application No. 117,035 discloses a group of 5-phenylthiazolidine-2,4-dione hypoglycemic agents of the formula ##STR2## where R.sup.c is lower alkyl, X.sup.a is F, Cl or Br and Y.sup.a is H, Cl, lower alkyl or lower alkoxy. U.S. Pat. No. 4,461,902 discloses certain 5-[(4-cyclohexylmethoxyphenyl) methyl]thiazolidine-2,4-dione hypoglycemic agents of the formula ##STR3## where R.sup.d is H or lower alkyl and Y.sup.b is an oxo or hydroxy group.